Kaposi's sarcoma associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and a proportion of Castelman's disease. KSHV encodes several cytokine-and chemokine-like proteins, including a homologue of interleukin-6 (IL-6). Viral (v) IL-6, produce predominantly during viral replication, exhibits approximately 25% amino acids identity to human and murine IL-6, suggesting that it may be the result of viral piracy of a useful cellular gene. Through experiments in vitro and in vivo, we have characterized the biological activities of vIL-6. Mice inoculated with vIL-6 displayed increased hematopoiesis in the myeloid, erythroid, and magakaryocytic lineages; plasmacytosis in the spleen and lymph nodes; hepatosplenomegaly, and polyclonal hypergammaglobulinemia. We determined that vIL-6 expressing fibroblasts give rise to tumors more rapidly than control cells, and linked increased tumor growth to vIL-6 induction of vascular endothelial growth factor (VEGF). In addition, using neutralizing antibodies directed at VEGF, we established that VEGF is required for experimental PEL development in mice. Using newly generated monoclonal antibodies against vIL-6, a sensitive vIL-6 ELISA was established. This assay permitted to evaluate serum vIL-6 levels in KSHV-associated diseases, and correlate circulating vIL-6 levels with disease progression and response to therapy. In vitro experiments were used to study vIL-6 receptor utilization. Unlike cellular IL-6, vIL-6 directly was found to bind to gp130. A panel of vIL-6-specific neutralizing antibodies were used as tools to dissect vIL-6 structure/function relationships. Thus, vIL-6, a multifunctional viral cytokine acting through the common gp130 receptor chain, is critically involved in the pathogenesis of certain KSHV associated diseases.